1. Field of the Invention
The present invention relates to the fields of genetics and molecular biology. More particular the invention relates to the identification of a gene on human chromosome 15 that is involved in Bardet-Biedl Syndrome (BBS), designated here as BBS4. Defects in this gene are associated with a variety of clinical symptoms including diabetes, hypogonadism, high blood pressure, renal cancer and other defects, retinal degeneration, congenital heart defects, limb deformity or polydactyly, mental retardation and obesity. Also provided are methods of therapy and mehtods of screening for therapeutic compositions.
2. Description of Related Art
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by mental retardation, obesity, pigmentary retinopathy, post-axial polydactyly and hypogonadism. A high frequency of renal abnormalities also is associated with this disorder. The mental retardation is often mild. Obesity begins early in infancy, and complications of obesity including diabetes mellitus and hypertension occur later in life. The associated retinal degeneration is usually severe and most patients become blind prior to 20 years of age. A recent report also provides evidence of an increased incidence of renal cell carcinoma (kidney cancer) as well as kidney malformations in BBS subjects.
The incidence of BBS varies between populations. A relatively high incidence of BBS is found in the mixed Arab populations of Kuwait and the Bedouin tribes throughout the Middle East, most likely due to the high rate of consanguinity in these populations. A relatively high frequency of BBS also has been reported in New Foundland.
BBS has been shown to display a remarkable degree of non-allelic genetic heterogeneity. The disorder was first shown to be genetically heterogenous based on mapping studies performed in large inbred Bedouin kindreds from Israel. The large number of traditional consanguineous marriages within these groups make it possible to identify inbred kindreds with multiple affected individuals that are large enough for independent linkage analysis.
Interest in the identification of genes causing BBS stem from the pleiotrophic nature of the disorder, and the fact that identification of BBS genes may provide important insight into biochemical and developmental pathways involved in common complex disorders including obesity and diabetes mellitus.
The first BBS locus (now referred to as BBS2) was mapped to chromosome 16 using a large inbred Bedouin kindred. Genetic heterogeneity was demonstrated when a second Bedouin BBS kindred did not map to the chromosome 16 locus. Subsequent studies in the second Bedouin kindred revealed linkage to chromosome 3 (BBS3). A third Bedouin kindred showed linkage to chromosome 15 (BBS4). To date, studies have demonstrated the existence of six BBS loci, and a seventh BBS locus has been postulated based on the fact that a few small BBS pedigrees do not appear to map to any of the known loci. A locus on chromosome 11 was assigned the designation BBS1 based on the fact that it appears to be the most common cause of BBS in some populations.
The first BBS gene (MKKS) was identified independently by two groups that hypothesized that mutations in the gene causing McKusick-Kaufman syndome (MKS) could also cause BBS. MKS is an autosomal recessive disorder characterized by post-axial polydactyly, as well as genital and cardiac anomalies. Mutations in the MKKS gene, a putative chaperonin gene, appear to account for approximately 10% of BBS cases. The mechanism by which mutations in the MKKS gene cause BBS has not been determined. Recently, a candidate BBS genes were identified on chromosomes 15 and 16 (WO 01/00825). Of these candidates, one refers to the 7 transmembrane receptor on chromosome 16.